文章：

儿童颅外实体瘤DNA修复通路的治疗靶向：现状及对免疫治疗的影响

Therapeutic Targeting of DNA Repair Pathways in Pediatric Extracranial Solid Tumors: Current State and Implications for Immunotherapy

原文发布日期：25 April 2024

DOI: 10.3390/cancers16091648

类型: Article

开放获取: 是

英文摘要：

DNA damage is fundamental to tumorigenesis, and the inability to repair DNA damage is a hallmark of many human cancers. DNA is repaired via the DNA damage repair (DDR) apparatus, which includes five major pathways. DDR deficiencies in cancers give rise to potential therapeutic targets, as cancers harboring DDR deficiencies become increasingly dependent on alternative DDR pathways for survival. In this review, we summarize the DDR apparatus, and examine the current state of research efforts focused on identifying vulnerabilities in DDR pathways that can be therapeutically exploited in pediatric extracranial solid tumors. We assess the potential for synergistic combinations of different DDR inhibitors as well as combinations of DDR inhibitors with chemotherapy. Lastly, we discuss the immunomodulatory implications of targeting DDR pathways and the potential for using DDR inhibitors to enhance tumor immunogenicity, with the goal of improving the response to immune checkpoint blockade in pediatric solid tumors. We review the ongoing and future research into DDR in pediatric tumors and the subsequent pediatric clinical trials that will be critical to further elucidate the efficacy of the approaches targeting DDR.

摘要翻译： 

DNA损伤是肿瘤发生的根本原因，而无法修复DNA损伤是许多人类癌症的标志。DNA通过DNA损伤修复（DDR）机制进行修复，该机制包括五个主要途径。癌症中的DDR缺陷为治疗提供了潜在靶点，因为携带DDR缺陷的癌症越来越依赖替代性DDR途径来维持生存。本文综述了DDR机制，并探讨了当前研究现状，重点关注识别DDR途径中的脆弱性，这些脆弱性可在儿童颅外实体瘤治疗中被利用。我们评估了不同DDR抑制剂之间以及DDR抑制剂与化疗药物联合应用的协同潜力。最后，我们讨论了靶向DDR途径的免疫调节意义，以及使用DDR抑制剂增强肿瘤免疫原性的潜力，旨在提高儿童实体瘤对免疫检查点阻断治疗的反应。我们回顾了当前及未来关于儿童肿瘤中DDR的研究，以及后续的儿童临床试验，这些试验对于进一步阐明靶向DDR治疗方法的疗效至关重要。

原文链接：

Therapeutic Targeting of DNA Repair Pathways in Pediatric Extracranial Solid Tumors: Current State and Implications for Immunotherapy